Royal College of Surgeons in Ireland
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Associations between type III interferons, obesity and clinical severity of COVID-19

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posted on 2025-07-01, 10:56 authored by Dana Alalwan, Alejandro Abner Garcia Leon, Gurvin Saini, Colette Gaillard, Riya Negi, Camille Heckmann, Grace Kenny, Eoin Feeney, Aoife G Cotter, Christine Kelly, Michael Carr, Eoghan De BarraEoghan De Barra, Obada Yousif, Mary Horgan, Corinna Sadlier, Alan Landay, Gabriel Gonzalez, Patrick W G Mallon, All Ireland Infectious Diseases Cohort Study

Introduction: Severe COVID-19 is characterized by hyperimmune host responses contributing to airway damage and acute respiratory distress syndrome. Type III interferons (IFN), including IFN lambda 4 (IFNλ4), expressed in individuals harboring the rs368234815-ΔG allele, are implicated in host immune responses to viral infections, including SARS-CoV-2.

Methods: We investigated associations between IFNλ4 expression through genotyping and COVID-19 disease severity in 853 laboratory-confirmed SARS-CoV-2 cases enrolled in the All-Ireland Infectious Diseases Cohort. Additionally, we measured plasma levels of Type I, II and III IFN using quantitative immunoassays along with IFNλ4 expression and COVID-19 disease severity in a sub-group [n=321 (37.6%)] with samples available within 10 days of symptom onset. IFNλ4 was expressed in 382 (44.8%) but expression was not significantly associated with COVID-19 disease severity.

Results: Within the sub-group, we found no consistent associations between IFNλ4 expression and circulating IFNs. However, we observed significantly increased expression of IFNλ1 and IFNλ2 in severe COVID-19 (P<0.01), with IFNλ2 remaining significantly associated after adjustment for age, sex, ethnicity, and comorbidities, including obesity (BMI≥30 kg/m2) (P<0.001). Interestingly, although IFNλ2 levels were significantly higher in subjects with obesity, the association between higher IFNλ2 and COVID-19 disease severity was only observed in individuals without obesity (P<0.01).

Conclusion: These data reveal an important role for IFNλ2 as an immune correlate that predicts COVID-19 disease severity, which may be masked in those with obesity.

Funding

Biological profiling in COVID-19 infection to characterise optimal therapeutic approaches

Science Foundation Ireland

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Smurfit Kappa

National Irish COVID-19 Biobank funded through the Health Research Board in Ireland (grant number NCov19BB-2021-1)

History

Data Availability Statement

The data that support the findings of this study manuscript can be requested from the All-Ireland Infectious Diseases Cohort Study group. However, the data can be made available on request subject to approval by a local ethics committee.

Comments

The original article is available at https://www.frontiersin.org/

Published Citation

Alalwan D, et al. Associations between type III interferons, obesity and clinical severity of COVID-19. Front Immunol. 2025;16:1516756.

Publication Date

22 April 2025

PubMed ID

40330483

Department/Unit

  • Beaumont Hospital
  • International Health and Tropical Medicine

Publisher

Frontiers Research Foundation

Version

  • Published Version (Version of Record)